The present invention relates to a process and intermediates for the production of N arylated isatins which are in turn used in the manufacture of N alkyl acridine sulfonamide chemiluminescent labels.
As disclosed in copending U.S. patent application Ser. No. 921,979 entitled Chemiluminescent Acridinium Salts filed on Oct. 22, 1986 by Mattingly et al. (the disclosure of which is incorporated herein by reference), such salts are useful in chemiluminescent immunoassays (CLIAs). In CLIAs, an antibody (or antigen) is labeled with a chemiluminescent moiety, and the labeled antibody (or antigen) is introduced to a sample containing the corresponding antigen (or antibody) to be detected or measured. Once the labeled antibody (or antigen) binds to the corresponding antigen (or antibody), the presence or amount of antigen (or antibody) in the sample can be determined, depending upon the type of assay format utilized. There are various assay formats: enzyme immunoassays, radioimmunoassays, fluorescent polarization immunoassays, and the like. Chemiluminescent immunoassays may thus match or exceed the sensitivity of radioimmunoassays (RIA), or enzyme immunoassays (EIA). [Kircka et al., Diagnostic Medicine, 1, 45 52 (1984].
Substituted acridine 9 carboxylic acid compounds have been demonstrated to be useful in CLIAs. To make such compounds, one can directly substitute an existing acridine compound. However, direct substitution often achieves low yields, forms many isomers, and often destroys other functional groups on the acridine rings. Substituted acridine 9 carboxylic acid compounds can also be prepared with the Jourdan Ullmann Goldberq synthesis and/or Chapman rearrangements. These procedures are labor intensive, unfortunately, and the substituted acridines formed from the cyclization of diphenyl amines often cannot be converted to the 9-carboxylic acids with known techniques. Finally, acridine 9 carboxylic acids can be prepared with a Pfitzinger rearrangement of isatins and ketones, with subsequent aromatization of the final ring on the acridine. But, low yields are often encountered, isomers are formed, and other functionalities on the acridine ring are often destroyed. This reaction scheme is also labor intensive and performed under harsh conditions. Accordingly, simple, economic processes for making acridines have been sought.
N-arylation of amines was disclosed by Barton et al "Metallic Copper Catalysts of N-Arylation of Amines," Tetrahedron Letters, Vol. 27, No. 31, pp. 3615-3618 (1986). However, amines are nucleophillic species, and are chemically reactive. By contrast, the amide (e.g. isatin) nitrogen is typically not considered nucleophillic. Presently, there is no good method of converting an unsubstituted isatin to the N-aryl isatin.